How Might Basic Research on
Low Dose Ionizing Radiation
Influence Future Radiation
Protection Programs
William F. Morgan, ...
Disclosures:
Member of NCRP, ICRP and
consultant for UNSCEAR - vested
interest in this issue.
But these are my opinions!
O...
Mans Radiation Burden
Cosmic rays
Air (radon)
Building material
Water
Food
Earth
Air travel
Testing fallout
TV & luminous
...
Computerized Tomography (10-30 mGy)
Hair Loss From Excessive Dose Of A CT Angiogram
CT Over-Exposure To A Young Patient
Fell from bed and complained of neck pain the following morning
Plain x-rays and then ...
US scientists are
warning that radiation
from controversial full-
body airport scanners
has been dangerously
underestimate...
This is why we have radiation
protection programs and what
radiation protection is all about!
So where does the informatio...
Most of our understanding of radiation effects
comes following a single acute exposure
Radiation Effects Research Foundation
(Hiroshima) a unique resource
~ 43% survivors still alive
In the laboratory acute ex...
Chernobyl, 1986
Protracted exposure (contamination)
Research Interests
Understanding effects of exposure
to low dose (<100mGy), low dose
rate ionizing radiation, the potentia...
How to extrapolate biological
effects at low doses to risk?
Are extrapolations from “high
dose” acute exposures
appropriat...
.01 .05 .1 101.0 4.0 100
A-bomb Survivor data
Supra-linearity
Dose (Sv)
Background
The dilemma for radiation protection: w...
Radiation Protection Considerations
Science is only one input to risk management
What are the other inputs?
Tradition
Not ...
Ionizing radiation Has The Potential
To Cause Detrimental Effects:
All radiation is bad and should be eliminated or
reduce...
On the other hand - complex biological systems have
physiological barriers against damage and disease. Primary
damage line...
The Radiendocrinator (ca. 1930)
Gold plated Radiendocrinator sold in its velvet lined pocket for $150. Beta-
gamma GM dete...
21
Societies Perception of Risk Differs
Epidemiology versus Biology
Epidemiology is fraught with
uncertainties…..So what is the
biological data (presumably the
me...
Any exposure has the potential for risk
Genetics
Environment
Diet
Lifestyle
The Current Paradigm For Risk
Conventional paradigm for radiation effects
25
In addition to targeted effects we must
consider the impact of non-targeted effects
Targeted cell
Survives and
prolifer...
Radiation-Induced Genomic Instability
Increased rate of genomic alterations in the
progeny of irradiated cells
Irradiation...
Clonally expand
Irradiate
Clonally expand
Metaphase analysis of
clonally expanded cells
Radiation-Induced Instability Can
Occur In Non-Targeted Cells:
Instability observed in cells not traversed
by an alpha par...
Radiation Induced Bystander Effects:
Effects observed in cells that were not
irradiated but were “bystanders” at the time ...
Radiation induced bystander effects:
Effects observed in cells that were not
irradiated but were “bystanders” at the time
...
Bystander effects in
an in vivo human
skin model (3D).
Belyakov et al. PNAS 102,
14203-7 (2005)
Beneficial? Eliminating da...
Implanted
LLC cells
Abscopal “Anti-Tumor” Effects In Vivo
5 x 10Gy
12 x 2Gy
fractionated
Significant delay in LLC cell gro...
76 year old male with back pain
Thoracic and abdominal CT scans
thoracic vertebral bone metastasis
and hepatocellular carc...
Precedent For Secreted Factor(s) In
Humans - Clastogenic Factors
Clastogenic Factors In Plasma From:
Accidentally irradiated individuals
Goh & Sumner, Radiation Res. 35, 171-181 (1968)
Th...
.01 .05 .1 101.0 4.0 100
A-bomb Survivor data
Supra-linearity
Dose (Sv)
Background
The dilemma for radiation protection: w...
Linear Non-Threshold is a Model/Hypothesis:
As such it has been used and abused!
Goal: public and worker protection
Assume...
Questions: How to design a system that limits risk?
How do we assign a potential human health risk?
Caveats: This system m...
Extrapolation From Experimental Systems:
Cells tissues organs man
What does in vitro cell culture tell us
about a response...
How do you communicate radiation risk when
the “so called experts” do not agree?
Disasters/crises make the news!
The publi...
Brenner & Hall; “Computed tomography - An increasing source of radiation
exposure” NEJM 357, 2277-2284 (2007)
Scott, Sande...
What About in the Low Dose Region?
BEIR VII cited 1386 peer reviewed publications
French Academie des Sciences cited 306 p...
My thoughts.
Epidemiology is unlikely to provide definitive
information - always “uncertainty”.
Radiobiology - mechanisms ...
OK - but given ionizing radiation is
probably the best studied human
carcinogen, how can we understand
its mechanism of ac...
Computation and
information
management
High-throughput
technologies
Hypothesis
Analysis Experiment
Why PNNL? Established e...
What is Systems Biology?
The quantitative study of biological networks and
pathways as integrated systems rather than as a...
52
A System Is A Result Of Interacting Parts:
An “interesting” part is one
for which the
consequences of
interaction is no...
53
Context Cannot Be Accurately Predicted
Without Multiple Sources Of Data
Well-designed studies with
appropriate controls...
Integrated Data Management
Data Storage
Data Discovery
(finding what is stored)
Data Integration
and Analysis
55
Key Event Networks connect molecular
networks to population dynamics
Edwards & Preston (2008), Tox Sci, 106(2):312-318
Hopefully PNNL’s systems
radiation biology program will
contribute to understanding the
long term health effects of
exposu...
And you 
don’t 
believe the 
media ??
Quiz: Which one is the child of
radiation exposed parent?
Comments and Questions?
wfmorgan@pnl.gov
How might basic research on low dose ionizing radiation influence future radiation protection programs morgan
How might basic research on low dose ionizing radiation influence future radiation protection programs morgan
How might basic research on low dose ionizing radiation influence future radiation protection programs morgan
How might basic research on low dose ionizing radiation influence future radiation protection programs morgan
How might basic research on low dose ionizing radiation influence future radiation protection programs morgan
How might basic research on low dose ionizing radiation influence future radiation protection programs morgan
How might basic research on low dose ionizing radiation influence future radiation protection programs morgan
How might basic research on low dose ionizing radiation influence future radiation protection programs morgan
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How might basic research on low dose ionizing radiation influence future radiation protection programs morgan

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How might basic research on low dose ionizing radiation influence future radiation protection programs morgan

  1. 1. How Might Basic Research on Low Dose Ionizing Radiation Influence Future Radiation Protection Programs William F. Morgan, Ph.D., D.Sc. Biological Sciences Division Pacific Northwest National Laboratory Richland, Washington USA
  2. 2. Disclosures: Member of NCRP, ICRP and consultant for UNSCEAR - vested interest in this issue. But these are my opinions! Outline of presentation: Why it is important My research interests Future directions
  3. 3. Mans Radiation Burden Cosmic rays Air (radon) Building material Water Food Earth Air travel Testing fallout TV & luminous watches Nuclear power plants (20%) Radioactive waste Diagnostic & therapeutic radiation* *> 200 million procedures/year (USA), 2 billion worldwide
  4. 4. Computerized Tomography (10-30 mGy)
  5. 5. Hair Loss From Excessive Dose Of A CT Angiogram
  6. 6. CT Over-Exposure To A Young Patient Fell from bed and complained of neck pain the following morning Plain x-rays and then a CT scan of neck ordered by ER CT table did not index (move) and radiologic technologist manually instituted 151 slices over a period of more than 1 hour The patient was successfully rescanned by another technician About 2-3 hours after the first CT attempt he developed a red line around his face at the level of the 151 CT scan slices
  7. 7. US scientists are warning that radiation from controversial full- body airport scanners has been dangerously underestimated and could lead to an increased risk of skin cancer - particularly in children. http://www.news.com.au/travel/news/naked- scanners-may-increase-cancer-risk
  8. 8. This is why we have radiation protection programs and what radiation protection is all about! So where does the information regarding the health effects of ionizing radiation come from?
  9. 9. Most of our understanding of radiation effects comes following a single acute exposure
  10. 10. Radiation Effects Research Foundation (Hiroshima) a unique resource ~ 43% survivors still alive In the laboratory acute exposures practical and convenient Radiation Dose Effect ?
  11. 11. Chernobyl, 1986 Protracted exposure (contamination)
  12. 12. Research Interests Understanding effects of exposure to low dose (<100mGy), low dose rate ionizing radiation, the potential consequences of such exposure(s) and how to translate these data to radiation risk.
  13. 13. How to extrapolate biological effects at low doses to risk? Are extrapolations from “high dose” acute exposures appropriate when human exposure is primarily chronic low dose exposure? Questions In the Context Of Radiation Protection
  14. 14. .01 .05 .1 101.0 4.0 100 A-bomb Survivor data Supra-linearity Dose (Sv) Background The dilemma for radiation protection: what is the scientific basis for radiation standards to protect the public from exposures to low levels of ionizing radiation (<0.1 Sv) where there are considerable uncertainties in the epidemiological data. Sub-linearity Hormesis LNT RadiationRelatedCancerRisk
  15. 15. Radiation Protection Considerations Science is only one input to risk management What are the other inputs? Tradition Not scaring people Politics Social values Economic considerations Technological considerations We have a long legacy of mistrust to deal with! Plus some widely diverging opinions Hormesis - tolerance - acceptance - total denial
  16. 16. Ionizing radiation Has The Potential To Cause Detrimental Effects: All radiation is bad and should be eliminated or reduced to a level as low as reasonably achievable (ALARA).
  17. 17. On the other hand - complex biological systems have physiological barriers against damage and disease. Primary damage linear with dose, secondary damage not. Cellular processes block damage propagation to clinical disease.
  18. 18. The Radiendocrinator (ca. 1930) Gold plated Radiendocrinator sold in its velvet lined pocket for $150. Beta- gamma GM detector ~ 200 mR/hr.
  19. 19. 21 Societies Perception of Risk Differs
  20. 20. Epidemiology versus Biology Epidemiology is fraught with uncertainties…..So what is the biological data (presumably the mechanisms) that can help us understand the potential effects of exposure to ionizing radiation?
  21. 21. Any exposure has the potential for risk Genetics Environment Diet Lifestyle The Current Paradigm For Risk
  22. 22. Conventional paradigm for radiation effects
  23. 23. 25 In addition to targeted effects we must consider the impact of non-targeted effects Targeted cell Survives and proliferates Secreted / shed factors gap junction communication Bystander cell
  24. 24. Radiation-Induced Genomic Instability Increased rate of genomic alterations in the progeny of irradiated cells Irradiation Manifests as: chromosomal rearrangements micronuclei aneuploidy delayed mutation (spectrum different) gene amplification cell killing Non clonal - not necessarily a fixed genetic change that is passed on.
  25. 25. Clonally expand Irradiate Clonally expand Metaphase analysis of clonally expanded cells
  26. 26. Radiation-Induced Instability Can Occur In Non-Targeted Cells: Instability observed in cells not traversed by an alpha particle Kadhim et al. Nature 355, 738-40 (1992) Shielded grid experiment Lorrimore et al. PNAS 95, 5730-3 (1998) secreted factor? cell to cell gap junction communication*? dead / dying cells*? *Not in our cell system
  27. 27. Radiation Induced Bystander Effects: Effects observed in cells that were not irradiated but were “bystanders” at the time of irradiation Single cell microbeam irradiation 1 cell irradiated Single  particle
  28. 28. Radiation induced bystander effects: Effects observed in cells that were not irradiated but were “bystanders” at the time of irradiation Single cell microbeam irradiation 1 cell irradiated gene expression mutation transformation micronuclei cell killing Why?
  29. 29. Bystander effects in an in vivo human skin model (3D). Belyakov et al. PNAS 102, 14203-7 (2005) Beneficial? Eliminating damaged or initiated cells Detrimental? Inducing damage in non-irradiated cells
  30. 30. Implanted LLC cells Abscopal “Anti-Tumor” Effects In Vivo 5 x 10Gy 12 x 2Gy fractionated Significant delay in LLC cell growth. Camphausen et al. Cancer Res. 63, 1990-1993 (2003)
  31. 31. 76 year old male with back pain Thoracic and abdominal CT scans thoracic vertebral bone metastasis and hepatocellular carcinoma 36Gy to the bone mass regression of hepatic lesions Ohba et al. Gut 43, 575-577, (1998) Retrospective analysis of serum concentration s of IL-1 beta, IL-2, IL-4, IL-6, HGF, and TNF-alpha Abscopal Effects:
  32. 32. Precedent For Secreted Factor(s) In Humans - Clastogenic Factors
  33. 33. Clastogenic Factors In Plasma From: Accidentally irradiated individuals Goh & Sumner, Radiation Res. 35, 171-181 (1968) Therapeutically irradiated individuals Hollowell & Littlefield, PSEBM. 129, 240-244 (1968) A-bomb survivors Pant & Kamada, Hiroshima J. Med. Sci. 26, 149-154 (1977) Chernobyl clean up workers Emerit et al., J. Cancer Res. Clin. Oncol. 120, 558-561 (1994) Children exposed after Chernobyl Emerit et al., Mutation Res. 373, 47-54 (1997) CF-Nelson rats Fagnet et al., Cancer Genet. Cytogenet. 12, 73-83 (1984) Patients with chromosome fragility syndromes Bloom syndrome, Fanconi anemia, XP and AT
  34. 34. .01 .05 .1 101.0 4.0 100 A-bomb Survivor data Supra-linearity Dose (Sv) Background The dilemma for radiation protection: what is the scientific basis for radiation standards to protect the public from exposures to low levels of ionizing radiation (<0.1 Sv) where there are considerable uncertainties in the epidemiological data. Sub-linearity Hormesis LNT RadiationRelatedCancerRisk
  35. 35. Linear Non-Threshold is a Model/Hypothesis: As such it has been used and abused! Goal: public and worker protection Assumes: Correctly that Tissues/organs differentially sensitive Risk varies with Age Sex Socio economic status Diet and lifestyle Genetic makeup and race Dose and dose rate Radiation quality
  36. 36. Questions: How to design a system that limits risk? How do we assign a potential human health risk? Caveats: This system must take into account : The most sensitive organ (breast)*? The most sensitive individual*? Where do you draw this line for regulatory purposes? * Ethical and legal questions Radiation resistant Radiation sensitive
  37. 37. Extrapolation From Experimental Systems: Cells tissues organs man What does in vitro cell culture tell us about a response in humans? What do in vivo models tell us about a response in humans - how do you extrapolate from an an animal model to the human population? Should you?
  38. 38. How do you communicate radiation risk when the “so called experts” do not agree? Disasters/crises make the news! The public reads/listens to the news. The public votes for politicians Politicians dictate policy Regulators have to implement the policy So where is the science? Lets take for example the increasing use of CT scans
  39. 39. Brenner & Hall; “Computed tomography - An increasing source of radiation exposure” NEJM 357, 2277-2284 (2007) Scott, Sanders, Mitchel & Boreham; “CT scans may reduce rather than increase the risk of cancer” J. Amer. Phys & Surg. 13, 8-11 (2008)
  40. 40. What About in the Low Dose Region? BEIR VII cited 1386 peer reviewed publications French Academie des Sciences cited 306 publications Overlap in publications cited = 68
  41. 41. My thoughts. Epidemiology is unlikely to provide definitive information - always “uncertainty”. Radiobiology - mechanisms not risk. The current system works - mortality data from nuclear power workers - “healthy workers” Hard to fault regulatory bodies for endorsing the middle ground of a LNT cancer risk model Life is dangerous - keep radiation in perspective.
  42. 42. OK - but given ionizing radiation is probably the best studied human carcinogen, how can we understand its mechanism of action? The Pacific Northwest National Laboratories Integrated Systems Biology Approach to Understanding Potential Effects Associated with Exposure to Ionizing Radiation.
  43. 43. Computation and information management High-throughput technologies Hypothesis Analysis Experiment Why PNNL? Established effort enables system’s biology To understand organisms from a “systems perspective” we must integrate experiments, analysis and modeling in a recursive manner
  44. 44. What is Systems Biology? The quantitative study of biological networks and pathways as integrated systems rather than as a set of isolated parts. Requires a long term investment in: Expertise biologists, chemists, physicists instrumentation & applied technology specialists mathematicians & computational scientists skilled laboratory technicians Time - infrastructure and expertise Technologies & development Ego suppression
  45. 45. 52 A System Is A Result Of Interacting Parts: An “interesting” part is one for which the consequences of interaction is non-trivial The sum of the system is greater than the sum of the parts. Biological systems are defined by multiple redundant and interdependent signaling networks and metabolic pathways
  46. 46. 53 Context Cannot Be Accurately Predicted Without Multiple Sources Of Data Well-designed studies with appropriate controls Gene expression data does not predict protein abundance Protein abundance data does not predict protein function Single time points do not provide directionality for correlation to functional outcomes Network reconstruction requires heterogeneous data for dose and dose rate-dependent and temporal measurements
  47. 47. Integrated Data Management Data Storage Data Discovery (finding what is stored) Data Integration and Analysis
  48. 48. 55 Key Event Networks connect molecular networks to population dynamics Edwards & Preston (2008), Tox Sci, 106(2):312-318
  49. 49. Hopefully PNNL’s systems radiation biology program will contribute to understanding the long term health effects of exposure to ionizing radiations But even if we do - will protection standards ever be based on scientific evidence?
  50. 50. And you  don’t  believe the  media ??
  51. 51. Quiz: Which one is the child of radiation exposed parent?
  52. 52. Comments and Questions? wfmorgan@pnl.gov

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